The effect and mechanism of inhibiting glucose-6-phosphate dehydrogenase activity on the proliferation of Plasmodium falciparum

Abstract

We screened >40,000 patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency and found that the G6PD Kaiping allele was under the most positive selection for fighting against malaria in the Chinese population. However, the mechanism is unknown. The current study was designed to investigate the anti-malarial effect and mechanism of G6PD deficiency. Dehydroepiandrosterone (DHEA) was utilised for inhibiting the G6PD activity of erythrocytes. Giemsa staining of blood smears and quantitative real-time PCR were used for the detection and quantification of Plasmodium falciparum infection. A transmission electron microscope was used to observe the structural changes of P. falciparum. An atomic force microscopy was used for the analyses of morphology, roughness and Young's Modulus of the infective erythrocyte membrane. When G6PD activity was inhibited by DHEA, the infection rate of P. falciparum decreased, its cell nucleus shrank, the cell organelles and metabolites were reduced gradually and the Young's Modulus of the erythrocyte membrane increased with increasing DHEA concentrations. These data indicated that Plasmodium multiplication would be inhibited in G6PD deficient erythrocytes because the Plasmodium organelles could not obtain enough nutrients, including ribose-5-phosphate and the reducing equivalent, NADPH. Moreover, the Young's Modulus of the erythrocyte membrane increased, which resulted in an increased membrane stiffness and decreased deformation. It was difficult for the merozoites to invade erythrocytes through endocytosis. Understanding these points will have a major effect on searching for new anti-malarial drug targets.

Keywords: Dehydroepiandrosterone; Glucose-6-phosphate dehydrogenase deficiency; Malaria; Mechanical properties; Plasmodium falciparum.